Polarization of epithelial cells with respect to their apical-basal axis as well as within the plane of the epithelium is crucial for proper organ function. Epithelial planar cell polarity (PCP) is characteristic for epithelia of species as diverse as humans and insects. For example, it is visible in the highly structured compound eye and on wing hairs of Drosophila, as well as on the scales of fish or in the mammalian inner ear. Sensory cells of the inner ear and the vestibular system produce an exquisite array of ordered stereocilia of defined length and arrangement. Genetic diseases affecting stereocilia formation and orientation lead to deafness and balance problems. The genetic network responsible for PCP establishment in Drosophila is very similar to those in humans and mice. Mutations in genes such as vangl2, celsr1 and myosinVIIA or their fly homologs stbm, fmi and zipper, all affect PCP. The short generation time and the powerful genetic and molecular tools available make Drosophila ideal for identifying components of PCP signaling, and the high degree of conservation makes it extremely likely these genes will also have corresponding roles in vertebrates. During PCP signaling, epithelial cells convert signals into positional information and modify their cytoskeletal apparatus in order to move or produce properly oriented structures. We will study the non-canonical Fz signaling pathway that has been shown to play a central role in this process and whose signaling activity is precisely regulated by components such as stbm/vangl2. We will 1) precisely characterize protein interactions of Stbm and define their mechanistic role and 2) identify missing components linking PCP signaling to changes in cell shape and the cytoskeleton using a combination of molecular and genetic approaches. The information gained from Drosophila will be used to design experiments in the mouse inner ear system that will be performed in collaboration with Dr. M. Kelley at the NIDCD. It will, therefore, be possible to extend our discoveries to mammalian ear development.